Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists.
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Yamamoto S, Kobayashi H, Kaku T, Aikawa K, Hara T, Yamaoka M, Kanzaki N, Hasuoka A, Baba A, Ito M
Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists.
Bioorg Med Chem. 2013 Jan 1;21(1):70-83. doi: 10.1016/j.bmc.2012.11.001. Epub 2012 Nov 12.
- PubMed ID
- 23199477 [ View in PubMed]
- Abstract
We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R(2)) of the pyrrolidine ring increased the AR binding affinity. The (2S,3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R(1)) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Bicalutamide Androgen receptor EC 50 (nM) >10000 N/A N/A Details Bicalutamide Androgen receptor IC 50 (nM) 330 N/A N/A Details Bicalutamide Androgen receptor IC 50 (nM) 54 N/A N/A Details Stanolone Androgen receptor IC 50 (nM) >10000 N/A N/A Details Stanolone Androgen receptor EC 50 (nM) 6.2 N/A N/A Details Stanolone Androgen receptor IC 50 (nM) 2.1 N/A N/A Details